Neisseria gonorrhoeae ciprofloxacin susceptibility testing and gyrA targets – Authors' reply
Authors: Daniel H F Rubin, Tatum D Mortimer, Yonatan H Grad
Journal: The Lancet Microbe (2023)

We agree with Jacob A Tickner and colleagues that diagnostics that predict Neisseria gonorrhoeae susceptibility to ciprofloxacin based on gyrA codon 91 are valuable tools in the effort to treat gonorrhoea and to address the challenge of antimicrobial resistance. But will these diagnostic tests always have the sensitivity and specificity that they have today? The premise of our work is that a diagnostic that guides antibiotic use will itself apply a selective pressure to escape from that diagnostic, under the same principle as antibiotics selecting for resistance.1Rubin DH Mortimer TD Grad YH Neisseria gonorrhoeae diagnostic escape from a gyrA-based test for ciprofloxacin susceptibility and the effect on zoliflodacin resistance: a bacterial genetics and experimental evolution study.Lancet Microbe. 2023; 4: e247-e254Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar Our in vitro results suggest that diagnostic escape is plausible. Moreover, this process promotes a pathway to ciprofloxacin resistance that also confers resistance to zoliflodacin, a novel antibiotic2Alm RA Lahiri SD Kutschke A et al.Characterization of the novel DNA gyrase inhibitor AZD0914: low resistance potential and lack of cross-resistance in Neisseria gonorrhoeae.Antimicrob Agents Chemother. 2015; 59: 1478-1486Crossref PubMed Scopus (58) Google Scholar in phase 3 trials. With gyrA codon 91-based diagnostics only recently coming into use, we are just at the start of the natural experiment to see what will happen in vivo. The more widespread the uptake of these diagnostics, the greater the selective pressure. When do potential adverse outcomes merit preventative action? Answering this question requires balancing the costs and benefits of action and inaction and decision making under uncertainty. We agree with Tickner and colleagues that it is important to weigh the likelihood of the outcome and to enumerate the costs and benefits—for example, the cost of adding a locus to a diagnostic test and the cost of waiting until the detection of clinical isolates with diagnostic escape mutations—to arrive at a reasoned strategy. We suggest that there is a clear need for vigilant monitoring for the emergence of diagnostic escape mutations through evaluation of treatment failures alongside expanded surveillance with phenotyping and genome sequencing of clinical isolates.3Hicks AL Kissler SM Lipsitch M Grad YH Surveillance to maintain the sensitivity of genotype-based antibiotic resistance diagnostics.PLoS Biol. 2019; 17e3000547Crossref PubMed Scopus (8) Google Scholar, 4Hicks AL Kissler SM Mortimer TD et al.Targeted surveillance strategies for efficient detection of novel antibiotic resistance variants.eLife. 2020; 9: 9Crossref Scopus (3) Google Scholar Surveillance for these mutations might be even more relevant with the rollout of zoliflodacin, as selection for resistance-conferring mutations in gyrB might also facilitate escape from gyrA codon 91-based diagnostics. YHG receives or has received support from Wellcome Trust, Pfizer, and Merck; receives or has received consulting fees from GlaxoSmithKline, Quidel, and the National Basketball Association; receives or has received payment for expert testimony from Merck; and serves on the advisory board for Day Zero Diagnostics. DHFR and TDM declare no competing interests. Neisseria gonorrhoeae diagnostic escape from a gyrA-based test for ciprofloxacin susceptibility and the effect on zoliflodacin resistance: a bacterial genetics and experimental evolution studyDiagnostic escape from gyrA codon 91 diagnostics could occur through either reversion of the gyrA allele or expansion of circulating lineages. N gonorrhoeae genomic surveillance efforts might benefit from including gyrB, given its potential for contributing to ciprofloxacin and zoliflodacin resistance, and diagnostic strategies that reduce the likelihood of escape, such as the incorporation of multiple target sites, should be investigated. Diagnostics that guide antibiotic therapy can have unintended consequences, including novel resistance determinants and antibiotic cross-resistance. Full-Text PDF Open AccessNeisseria gonorrhoeae ciprofloxacin susceptibility testing and gyrA targetsMolecular assays for identifying ciprofloxacin susceptibility via the Neisseria gonorrhoeae gyrA codon 91 are now available. Rubin and colleagues1 present data exploring the possibility of diagnostic escape from gyrA codon 91-based ciprofloxacin susceptibility testing, and conclude that escape could occur through either reversion of the gyrA allele or expansion of circulating N gonorrhoeae lineages. The authors also highlight concerns over coselection of zoliflodacin resistance via alternative mechanisms such as gyrB D429N. Full-Text PDF Open Access